Ester or amide derivatives

Details Ester or amide derivatives Ester or amide derivatives

2003-02-28

2004-11-23

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S155000, C546S156000, C514S312000, C514S313000, C514S314000

Reexamination Certificate

active

06822098

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel ester or amide derivative, particularly an ester or amide derivative of 4-oxo-1,4-dihydroqunoline-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and a drug composition containing it as an active ingredient, particularly a preventive or remedy for
Helicobacter pylori
infectious diseases.
BACKGROUND ART
Helicobacter pylori
is a pathogenic bacterium discovered in 1983 and is called a background pathogenic factor of peptic ulcers (such as gastric ulcer and duodenal ulcer), inflammations (such as gastritis), diseases of upper digestive tracts such as gastric cancer, MALT (mucosa-associated lymphoid tissue) lymphoma, or chronic heart disease. At present, studies on the therapy of
Helicobacter pylori
infectious diseases are being actively made. As the therapy, there are many reports for the purposes of bacterial elimination and prevention of recurrence, as described below. For example, there is numerated administration of a single drug of, e.g., bismuth, antibiotic, proton pump inhibitor (PPI), or anti-ulcer agent, or polypharmacy (such as two-drug therapy and three-drug therapy) comprising a combination of the foregoing drugs (see
Internal Medicine, Special Issue
, Vol. 78 (1), 1996, by Nankodo). However, these therapies still involve many problems to be solved, such as high frequency of administration of the drug(s), necessity of administration of a lager amount of the drug(s) than the regular dose, crisis of diarrhea or constipation by administration of the drug(s), and generation of resistant bacteria.
As an anti-helicobacter pylori agent, EP811613 discloses derivatives of 4-oxo-1,4-dihydroquinoline or naphthyridine in terms of the following general formula. In the general formula, the substituent (R
2
group) at the 2-position of the ring is a C
1
to C
10
alkyl group, a (C
1
to C
10
alkyl)phenyl group, a C
2
to C
10
alkenyl group, a (C
2
to C
10
alkenyl)phenyl group, a C
2
to C
10
alkynyl group, a (C
2
to C
10
alkynyl)phenyl group, a phenyl group, a naphthyl group, a furyl group, a thiophenyl group, or a pyridyl group.
Further, JP-A-10-132784 discloses the following 3-methyl-4-oxo-1,4-dihydroquinone derivative as an anti-helicobacter pylori agent, in which, however, the substituent at the 2-position is a nonenyl group.
However, creation of a compound having a stronger anti-helicobacter pylori action by single and oral administration is being demanded.
On the other hand, as derivatives of a 3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, in DE1913466
, Pol. J. Pharmacol. Pharm
., 33(5), 539-544, 1981
, Indian. J. Pharm
., 39(1), 13-15, 1977
, J. Indian Chemical Society
, 50(3), 217-218, 1973, and
J. Indian Chemical Society
, 51(11), 967-969, 1974, there are disclosed compounds having an ethoxycarbonyl group or a (substituted or unsubstituted) NH
2
—NH—CO— group at the 2-position of the quinoline ring. However, any of these compounds are merely a synthesis intermediate or are merely reported that they have an anti-amoeba activity. These documents neither disclose nor suggest their anti-helicobacter pylori activity.
DISCLOSURE OF THE INVENTION
We, the present inventors made extensive and intensive investigations with respect to compounds having an anti-helicobacter pylori activity. As a result, it has been found that novel ester or amide derivatives of 4-oxo-1,4-dihydroquinoline-2-carboxylic acid, which are different in terms of structure from the conventional compounds in the point that on the 1,4-dihydroquinoline ring or 1,4-dihydronaphthyridine ring, not only a substituent at the 2-position is an ester residue or a substituted amide group, but also a substituent at the 3-position is an alkyl group, (1) have a strong and selective anti-bacterial action against
Helicobacter pylori
, (2) have a strong anti-bacterial action against
Helicobacter pylori
within digestive tracts by oral administration to mammals, and (3) are useful in the bacterial elimination therapy against patients infected with
Helicobacter pylori.
Specifically, the invention relates to a novel ester or amide derivative represented by the following general formula (I) or a salt thereof:
wherein:
X
1
to X
4
each independently represents C or N, provided that at least one of X
1
to X
4
represents C;
Y represents O or NH;
R
1
represents a C
1
to C
6
alkyl group;
R
2
represents (a) a C
1
to C
10
alkyl group, provided that when X represents O, R
2
represents a C
3
to C
10
alkyl group, or (b) an aryl-C
1
to C
10
alkyl group, a heteroaryl-C
1
to C
10
alkyl group, or a cycloalkyl-C
1
to C
10
alkyl group, provided that any carbon-carbon bond of the C
1
to C
10
alkyl group may be inserted by —O—, —NR
8
—, or —S(O)
n
—, wherein R
8
represents H or a C
1
to C
6
alkyl group, and n is 0, 1 or 2, and that the aryl, heteroaryl and cycloalkyl may each be substituted with from one to three of halogen, C
1
to C
6
alkyl, C
1
to C
6
alkyl-O—, nitro, cyano, amino, hydroxycarbonyl, C
1
to C
6
alkyl-NH—, or di-C
1
to C
6
alkyl=N—;
R
3
represents H, a C
1
to C
6
alkyl group, an aryl-C
1
to C
6
alkyl group, a heteroaryl-C
1
to C
6
alkyl group, a cycloalkyl-C
1
to C
6
alkyl group, an aryl group, a heteroaryl group, or a cycloalkyl group, provided that the aryl, heteroaryl and cycloalkyl may each be substituted with from one to three of halogen, C
1
to C
6
alkyl, C
1
to C
6
alkyl-O—, nitro, cyano, amino, hydroxycarbonyl, C
1
to C
6
alkyl-NH—, or di-C
1
to C
6
alkyl=N—; and
R
4
to R
7
may be the same or different and each represents H, a halogen, a nitro group, a cyano group, an amino group, a hydroxycarbonyl group, a C
1
to C
6
alkyl group, a C
1
to C
6
alkyl-O— group, a C
1
to C
6
alkyl-NH group, or a di-C
1
to C
6
alkyl=N— group,
provided that in the case where X
1
to X
4
each represents N, R
4
to R
7
to be bound thereto are not present and that R
3
and R
4
may be taken together to form a linear or branched C
1
to C
8
alkylene which may be inserted by N, O or S.
Also, the invention relates to a drug composition comprising the ester or amide derivative represented by the foregoing general formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, a particularly a drug composition as a preventive or remedy for
Helicobacter pylori
infectious diseases.
The compound (I) of the invention is structurally characterized in that a substituent at the 2-position of the 1,4-dihydroquinoline ring or 1,4-dihydronaphthyridine ring is an ester residue or an substituted amide group and is superior to the known compounds having a hydrocarbon group as the substituent at the 2-position in the point that it undergoes strong bacterial elimination against
Helicobacter pylori
within digestive tracts by oral administration to mammals.
The compound (I) of the invention will be hereunder described in detail.
Examples of the “halogen” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The term “alkyl” means a linear or branched saturated hydrocarbon group. Specific examples of the C
1
to C
10
alkyl include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, and structural isomers thereof (such as an isopropyl group). Specific examples of the C
1
to C
6
alkyl include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and structural isomers thereof (such as an isopropyl group). Specific examples of the C
6
to C
8
alkyl include a hexyl group, a heptyl group, an octyl group, and structural isomers thereof (such as a methylhexyl group).
The term “alkylene” means a divalent group resulted from removal of hydrogen from the foregoing alkyl. Specific examples of the C
1
to C
8
alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, and structural isomers thereof (such as 2-methylpropylene).
The term “aryl” means an aromati

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